Low-Dose Radiation Therapy for COVID-19: Promises and Pitfalls.

The coronavirus disease-2019 (COVID-19) pandemic caused by SARS-CoV-2 has exacted an enormous toll on healthcare systems worldwide. The cytokine storm that follows pulmonary infection is causally linked to respiratory compromise and mortality in the majority of patients. The sparsity of viable treatment options for this viral infection and the sequelae of pulmonary complications have fueled the quest for new therapeutic considerations. One such option, the long-forgotten idea of using low-dose radiation therapy, has recently found renewed interest in many academic centers. We outline the scientific and logistical rationale for consideration of this option and the mechanistic underpinnings of any potential therapeutic value, particularly as viewed from an immunological perspective. We also discuss the preliminary and/or published results of prospective trials examining low-dose radiation therapy for COVID-19.

A Comprehensive Analysis of Near-Contact Photobiomodulation Therapy in the Host-Bacteria Interaction Model Using 3D-Printed Modular LED Platform.

One well-studied bacterial factor recognized by the host immune system is lipopolysaccharides (LPS) that stimulate host cells, resulting in cell inflammation. Although photobiomodulation (PBM) therapy demonstrates its potency on anti-inflammatory activity, the complete mechanism of action in the host-bacteria interaction model is still elusive. In addition, many studies were performed regarding a distance between the light source and biological sample (non-contact therapy) that may result in disparate reports on the efficacy of PBM therapy. Thus, it is critical to clearly understand the effect of this approach to maximize efficacy and minimize side effects. Here, a custom-built light-emitting diode (LED) platform that mimics near-contact therapy is developed. The effect and mechanism of PBM therapy on epithelial cells in response to LPS is systematically investigated under various conditions (wavelength, irradiation-time, pulse-frequency). The data show that the irradiation of near-infrared (NIR-LED) significantly improves the viability of inflamed cells. It reveals that NIR-LED inhibits the production of reactive oxygen species by regulating the Nox4-NF-κB pathway. Interestingly, however, high-pulse frequency stimulus causes the collapse of the mitochondrial membrane potential (ΔΨm) of cells, resulting in cell death. These results suggest that the optimized "PBM condition" is critical to assist the healthy immune system of the host against bacterial invasion.

Local adaptation of a parasite to solar radiation impacts disease transmission potential, spore yield, and host fecundity.

Environmentally transmitted parasites spend time in the abiotic environment, where they are subjected to a variety of stressors. Learning how they face this challenge is essential if we are to understand how host-parasite interactions may vary across environmental gradients. We used a zooplankton-bacteria host-parasite system where availability of sunlight (solar radiation) influences disease dynamics to look for evidence of parasite local adaptation to sunlight exposure. We also examined how variation in sunlight tolerance among parasite strains impacted host reproduction. Parasite strains collected from clearer lakes (with greater sunlight penetration) were most tolerant of the negative impacts of sunlight exposure, suggesting local adaptation to sunlight conditions. This adaptation came with both a cost and a benefit for parasites: parasite strains from clearer lakes produced relatively fewer transmission stages (spores) but these strains were more infective. After experimental sunlight exposure, the most sunlight-tolerant parasite strains reduced host fecundity just as much as spores that were never exposed to sunlight. Sunlight availability varies greatly among lakes around the world. Our results suggest that the selective pressure sunlight exposure exerts on parasites may impact both parasite and host fitness, potentially driving variation in disease epidemics and host population dynamics across sunlight availability gradients.

Red light delays programmed cell death in non-host interaction between Pseudomonas syringae pv tomato DC3000 and tobacco plants.

Light modulates almost every aspect of plant physiology, including plant-pathogen interactions. Among these, the hypersensitive response (HR) of plants to pathogens is characterized by a rapid and localized programmed cell death (PCD), which is critical to restrict the spread of pathogens from the infection site. The aim of this work was to study the role of light in the interaction between Pseudomonas syringae pv. tomato DC3000 (Pto DC3000) and non-host tobacco plants. To this end, we examined the HR under different light treatments (white and red light) by using a range of well-established markers of PCD. The alterations found at the cellular level included: i) loss of membrane integrity and nuclei, ii) RuBisCo and DNA degradation, and iii) changes in nuclease profiles and accumulation of cysteine proteinases. Our results suggest that red light plays a role during the HR of tobacco plants to Pto DC3000 infection, delaying the PCD process.

BmNPV infection correlates with the enhancement of the resistance of Bombyx mori cells to UV radiation.

At present, the effect of ultraviolet (UV) radiation on the interaction between Bombyx mori nucleopolyhedrovirus (BmNPV) and host remains unclear. In the current study, UV treatment significantly reduced the activity of BmNPV budded viruses (BVs), and UV-damaged BmN cells were not conducive to BmNPV proliferation. BmNPV infection significantly reduced the viability of host cells, but increased the viability of high-dose UV-treated host cells. Furthermore, the quantitative reverse-transcription PCR (qPCR) results suggested that BmNPV and Bombyx mori might mutually use the same DNA repair proteins for repairing UV-induced damage and BmNPV infection promote the ability of host cells to repair UV-induced damage.

Light regulation of coccolithophore host-virus interactions.

Viruses that infect photoautotrophs have a fundamental relationship with light, given the need for host resources. We investigated the role of light on Coccolithovirus (EhV) infection of the globally distributed coccolithophore, Emiliania huxleyi. Light was required for EhV adsorption, and viral production was highest when host cultures were maintained in continuous light or at irradiance levels of 150-300 µmol m-2  s-1 . During the early stages of infection, photosynthetic electron transport remained high, while RuBisCO expression decreased concomitant with an induction of the pentose phosphate pathway, the primary source of de novo nucleotides. A mathematical model developed and fitted to the laboratory data supported the hypothesis that EhV replication was controlled by a trade-off between host nucleotide recycling and de novo synthesis, and that photoperiod and photon flux could toggle this switch. Laboratory results supported field observations that light was the most robust driver of EhV replication within E. huxleyi populations collected across a 2000 nautical mile transect in the North Atlantic. Collectively, these findings demonstrate that light can drive host-virus interactions through a mechanistic interplay between host metabolic processes, which serve to structure infection and phytoplankton mortality in the upper ocean.

The Paradoxical Effects of Different Hepatitis C Viral Loads on Host DNA Damage and Repair Abilities.

Hepatitis C virus (HCV)-induced hepatic stress is associated with increased oxidative DNA damage and has been implicated in hepatic inflammation. However, HCV infection and replication are uneven and vary among individual hepatocytes. To investigate the effect of the viral load on host DNA damage, we used an Enhanced Yellow Fluorescent Protein gene (EYFP)-tagged HCV virus to distinguish between HCV intracellular high viral load (HVL) cells and low viral load (LVL) cells. The cell sorting efficiency was confirmed by the high expression of the HCV polyprotein. We found DNA damage γ-H2AX foci in the HVL population. Comet assays demonstrated that HVL was related to the extent of the DNA strand breaks. Surprisingly, the DNA qPCR arrays and western blotting showed that the damage-related genes GPX2, MRE11, phospho-ATM, and OGG1 were significantly up-regulated in LVL cells but inversely down-regulated or consistently expressed in HVL cells. The colony survival assay to examine the repair abilities of these cells in response to irradiation showed that the LVL cells were more resistant to irradiation and had an increased ability to repair radiation-induced damage. This study found that intracellular viral loads drove cellular DNA damage levels but suppressed damage-related gene expression. However, the increase in damage-related gene expression in the LVL cells may be affected by ROS from the HVL cells. These findings provide new insights into the distinct DNA damage and repair responses resulting from different viral loads in HCV-infected cells.

Human Papilloma Virus as a Biomarker for Personalized Head and Neck Cancer Radiotherapy.

A dramatic increase in the incidence of HPV-related oropharyngeal cancer has been reported in some parts of the western world over the past 30 years. They constitute a clinically distinct subgroup of cancers in terms of molecular biology, patient characteristics, and treatment outcome. This chapter describes the molecular characteristics, epidemiology, and demographics of the HPV-related head and neck cancers and discuss available methods to detect HPV-related tumours. The impact of HPV-related biomarkers in clinical studies on radiotherapy only, altered fractionation, modulation of hypoxia, and concurrent chemo- or bio-radiotherapy are reviewed as well as the perspectives of de-escalation and immune-modulation are discussed.

Stress promotes Arabidopsis - Piriformospora indica interaction.

The endophytic fungus Piriformospora indica colonizes Arabidopsis thaliana roots and promotes plant performance, growth and resistance/tolerance against abiotic and biotic stress. Here we demonstrate that the benefits for the plant increase when the two partners are co-cultivated under stress (limited access to nutrient, exposure to heavy metals and salt, light and osmotic stress, pathogen infection). Moreover, physical contact between P. indica and Arabidopsis roots is necessary for optimal growth promotion, and chemical communication cannot replace the physical contact. Lower nutrient availability down-regulates and higher nutrient availability up-regulates the plant defense system including the expression of pathogenesis-related genes in roots. High light, osmotic and salt stresses support the beneficial interaction between the plant and the fungus. P. indica reduces stomata closure and H2O2 production after Alternaria brassicae infection in leaves and suppresses the defense-related accumulation of the phytohormone jasmonic acid. Thus, shifting the growth conditions toward a stress promotes the mutualistic interaction, while optimal supply with nutrients or low stress diminishes the benefits for the plant in the symbiosis.

Similar cisplatin sensitivity of HPV-positive and -negative HNSCC cell lines.

Patients with HPV-positive head and neck squamous cell carcinoma (HNSCC) show better survival rates than those with HPV-negative HNSCC. While an enhanced radiosensitivity of HPV-positive tumors is clearly evident from single modality treatment, cisplatin is never administered as monotherapy and therefore its contribution to the enhanced cure rates of HPV-positive HNSCC is not known. Both cisplatin and radiotherapy can cause severe irreversible side effects and therefore various clinical studies are currently testing deintensified regimes for patients with HPV-positive HNSCC. One strategy is to omit cisplatin-based chemotherapy or replace it by less toxic treatments but the risk assessment of these approaches remains difficult. In this study we have compared the cytotoxic effects of cisplatin in a panel of HPV-positive and -negative HNSCC cell lines alone and when combined with radiation.While cisplatin-treated HPV-positive strains showed a slightly stronger inhibition of proliferation, there was no difference regarding colony formation. Cellular responses to the drug, namely cell cycle distribution, apoptosis and γH2AX-induction did not differ between the two entities but assessment of cisplatin-DNA-adducts suggests differences regarding the mechanisms that determine cisplatin sensitivity. Combining cisplatin with radiation, we generally observed an additive but only in a minority of strains from both entities a clear synergistic effect on colony formation. In summary, HPV-positive and -negative HNSCC cells were equally sensitive to cisplatin. Therefore replacing cisplatin may be feasible but the substituting agent should be of similar efficacy in order not to jeopardize the high cure rates for HPV-positive HNSCC.

Host-microbe cross talk in cancer therapy.

PURPOSE OF REVIEW: Microbiota secrete a multitude of factors that either confer virulence or promote colonization because they are continuously challenged by host immune responses. The dynamic interplay between the host's immune response and microbiota eventually determines the outcome for the host: health or disease. Toll-like receptors (TLRs) play a key role in this interplay as they can recognize both microbial and host-derived ligands on the basis of the context in which recognition occurs. RECENT FINDINGS: Evidence is accumulating that conventional cancer therapies alter interactions and cross talks between the host and microbiota. This has been shown for intestinal mucositis, a common side-effect of various cancer therapies. Advances have been made in the development of new and less toxic cancer strategies. One promising field is immunotherapy on the basis of TLR activation through recognition of microbial-associated molecular patterns. SUMMARY: Evidence is emerging, indicating that existing cancer therapies have implications on the composition and functionality of the host-microbiota environment. This may favor the colonization of pathogens and build up the overall toxicity of the drug. Exploitation of the host-microbiota cross talks mediated by TLRs is an emerging and promising field in the search for new, less toxic anticancer strategies.

Prognostic value of human papillomavirus in anal squamous cell carcinoma.

PURPOSE: Anal cancer is an uncommon malignancy, but its incidence is increasing worldwide. Chemoradiation is the standard primary treatment for patients with loco-regional limited disease. However, once patients develop metastatic spread, the prognosis is very poor. Human papillomavirus (HPV) is present in around 80 % of anal cancers, but its prognostic and/or predictive value is essentially unknown in this disease. METHODS: We retrospectively evaluated 50 patients with the diagnosis of anal squamous cell carcinoma treated at our institution with combined chemoradiotherapy for loco-regional limited disease. HPV status was evaluated from paraffin-embedded tumor tissues collected at the time of diagnosis by a polymerase chain reaction analysis. RESULTS: Among 50 patients, 42 (84 %) were HPV-positive. Thirty-two (64 %) patients were positive to genotype 16, two (4 %) to genotype 18, and three (6 %) to both 16 and 18. Lymph nodal involvement and clinical stage at diagnosis were more advanced for HPV-positive patients. After a median follow-up of 4 years (range 0.4-13.8), 46 (92 %) patients were alive. Overall, eight patients relapsed: One regional, one loco-regional, and six distant recurrences were observed. Four patients died of metastatic disease. Five-year disease-free survival (DFS) in HPV-positive and HPV-negative patients was 92.5 and 50.0 %, respectively (P < 0.01). In multivariate analysis, HPV-positivity was associated with a statistically significant better 5-year DFS (HR HPV+ vs HPV- 0.10; 95 % CI 0.02-0.50). Five-year overall survival in HPV-positive and HPV-negative patients was 93.3 and 66.7 %, respectively (P = 0.12). CONCLUSIONS: In our study, HPV-positive anal cancers had a statistically significant improved DFS compared to HPV-negative group.

EFFECTS OF ELECTROMAGNETICALLY SIGNALIZED MEDIA ON HOST-PATHOGEN INTERACTION.

Up to date, limited data are available about electromagnetic phase signaling effects on host-pathogen interactions during the postharvest of horticultural commodities. Inspired by the last striking works on water physics, quantum signaling through phase transfer and its impact on biological and histological structures, we studied the effect of different electromagnetic signals on pome blue mold (Penicillium expansum) pathogenesis. Tags with different electromagnetic-signals (EmS) were used to generate 3 Coherent Electro Dynamic (CED) environments. Artificially wounded 'Coscia' pears, placed onto 3 EmS tags (QF, QA and QR), were employed for the in vivo experiment. Whereas, a set of wounded-fruit placed onto an un-electromagnetic-signalized tag (QN) or kept without tag were used as blank or control, respectively. Inoculation was performed 2 or 24 h post-wounding with P. expansum conidia. The same tags placed under Petri dishes containing dot-inoculated PDA served for the in vitro experiment. Both experiments performed at 25 degrees C endured 7 days. The percentage of infected wounds was calculated and the radial growth measured in vitro. Concerning the in vivo experiment, 100% of control and blank fruit inoculated 2 h post-wounding was infected after 5 days, while, 97% after 7 days, when inoculation occurred 24 h post-wounding. Compared to control and blank, the pathogenesis in fruit placed on the EmS tags resulted inhibited, and when fruit was inoculated 2 h post-wounding, the infection degree on QF, QA and QR tags resulted 19, 52 and 64%, respectively. The degree for the same EmS tags was significantly lower when fruit was inoculated 24 h post-wounding (9, 32 and 42%, respectively). The in vitro experiment evidenced a notable inhibition of the radial growth by all EmS tags in comparison to control and blank (51 mm), while the QF tag provided the greatest inhibition (12 mm).

Valoración de anticuerpos con reactividad cruzada patógeno-huésped en pacientes con diferentes estadios de cardiopatía chagásica crónica / Assessment of cross-reactive host-pathogen antibodies in patients with different stages of chronic Chagas disease

Introducción y objetivos. La infección por Trypanosoma cruzi induce una respuesta autoinmunitaria humoral contra diferentes antígenos del huésped. En especial, los anticuerpos que presentan reactividad cruzada con antígenos del miocardio tienen un papel importante en el desarrollo de las formas graves de la cardiopatía chagásica crónica. En este trabajo se analiza la asociación del estadio clínico de la enfermedad con la presencia de autoanticuerpos en pacientes con cardiopatía chagásica crónica. Métodos. Estudio transversal con pacientes con serología positiva para enfermedad de Chagas, categorizados en tres grupos según la clasificación de cardiopatía chagásica de Storino et al. Se realizó a todas las personas incluidas un examen clínico completo y se usaron las muestras de suero para cuantificar los autoanticuerpos. Resultados. Todos los pacientes presentaron cantidades detectables de anti-p2Beta y anti B13; el anti-Na-K-ATPasa fue negativo en todos los casos. No se halló asociación significativa entre las alteraciones electrocardiográficas y los valores de autoanticuerpos. Los pacientes con cardiopatía chagásica en estadio III presentaron mayor concentración de anti-B13 y riesgo de mortalidad alto, lo que muestra una clara asociación entre el estadio de la enfermedad y la puntuación de mortalidad. Conclusiones. La concentración del autoanticuerpo anti-B13 fue significativamente mayor en los pacientes con cardiopatía chagásica en estadio III , lo que indica que este anticuerpo puede estar involucrado en la progresión de la enfermedad y podría usarse como marcador de mal pronóstico respecto a la afección cardiaca. Los resultados revelan también una importante correlación entre el anti-B13 y la insuficiencia cardiaca sintomática y la cardiomiopatía dilatada (AU)

Introduction and objectives. Trypanosoma cruzi infection has been shown to induce humoral autoimmune responses against host antigens tissues. Particularly, antibodies cross-reacting with myocardial antigens may play a role in the development of the severe forms of chronic Chagas disease. The aim of this study was to determine the association between clinical stage of the disease and the presence of autoantibodies in patients with chronic Chagasic disease. Methods. We performed a cross-sectional study in T. cruzi-seropositive patients divided into 3 groups according to the classic classification of chronic Chagas heart of Storino et al. All participants underwent complete clinical examination and their sera were used to measure autoantibody levels. Results. All patients had detectable levels of anti-p2Beta and anti-B13 autoantibodies but none had anti-Na-K-ATPase antibodies. No association was observed between electrocardiographic conduction disturbances and autoantibody levels. Patients with chronic Chagas disease stage III had the highest levels of anti-B13 antibodies and a high risk of mortality score, showing a clear association between disease stage and this score. Conclusions. Anti-B13 antibodies were significantly higher in chronic Chagas disease stage III patients, suggesting that these antibodies may be involved in disease progression and that they might be a useful marker of poor prognosis in terms of heart compromise. Our results also reveal an important correlation between the level of anti-B13 autoantibodies and symptomatic heart failure and/or dilated cardiomyopathy (AU)

Polyomavirus inactivation - a review.

Polyomavirus inactivation has been studied since the 1950s when it became apparent that certain polio vaccines were contaminated with SV40. Relatively high temperatures (≥70 °C) are required to effect thermal inactivation of the polyomaviruses. The chemical inactivants that are effective (ß-propiolactone, ethanol, sodium hydroxide, and formaldehyde) are those that have displayed efficacy for other small, non-enveloped viruses, such as the circoviruses. Low pH inactivation can be effective, especially at pH at or below 3 and at higher temperatures. Polyomaviruses are more resistant to UV-C irradiation than are other small non-enveloped viruses such as the parvoviruses and caliciviruses. The efficacy of photodynamic inactivation of polyomaviruses is very much dye-dependent, with toluidine blue, acridine orange, and methylene blue dyes being effective photosensitizers. Ionizing radiation can be effective, depending on the conditions employed and the inactivation matrix. Inactivation of the oncogenic properties of the polyomaviruses may require higher doses of inactivant than those required to inactivate infectivity. While the polyomaviruses are considered to be highly resistant to inactivation, the degree of resistance is dependent upon the specific approach under consideration. For certain approaches, such as UV-C and gamma-irradiation, the polyomaviruses appear to be more resistant than other small non-enveloped viruses.

Solar radiation decreases parasitism in Daphnia.

Climate change and variation in atmospheric ozone are influencing the intensity of ultraviolet radiation (UVR) reaching ecosystems. Changing UVR regimes, in turn, may alter epidemics of infectious disease. This possibility hinges on the sensitivity of epidemiologically relevant traits of host and parasite to UVR. We address this issue using a planktonic system (a zooplankton host, Daphnia dentifera, and its virulent fungal parasite, Metschnikowia bicuspidata). Controlled laboratory experiments, coupled with in situ field incubations of spores, revealed that quite low levels of UVR (as well as longer wavelength light) sharply reduced the infectivity of fungal spores but did not affect host susceptibility to infection. The parasite's sensitivity to solar radiation may underlie patterns in a lake survey: higher penetration of solar radiation into lakes correlated with smaller epidemics that started later in autumn (as incident sunlight declined). Thus, solar radiation, by diminishing infectivity of the parasite, may potently reduce disease.